Since American scientist B. Rosenborg accidentally discovered that cisplatin has antitumor activity in 1965, the synthesis, application and research of platinum-based anticancer drugs have been developed rapidly. As compared with traditional cytotoxic antitumor drugs, platinum-based anti-tumor drugs have a unique mechanism of action, which mainly targets DNA. Platinum-based anti-tumor drugs are hydrolyzed after entering into cells to form positively charged platinum hydrates with high activity, which react with nucleic acid and protein to form a DNA intrastrand and/or interstrand conjugate, thereby resulting in a change in the secondary structure of DNA, hindering the transcription and replication of DNA and eventually leading to apoptosis. At present, cis-dichlorodiamine platinum (i.e., Cisplatin), cis-1,1-cyclobutane dicarboxylic acid diamine platinum (i.e., Carboplatin), cis-oxalic acid-(trans-(−)-1,2-cyclohexanediamine)platinum (i.e., Oxaliplatin), Nedaplatin, Eptaplatin, Lobaplatin, and the like, have been successfully developed. Platinum-based anti-tumor drugs have characteristics such as wide anti-cancer spectrum, strong activity, no cross tolerance. There is statistical data showing that in 70% to 80% of all chemotherapy regimens, platinums are dominated, or involved in composition. However, platinum-based anti-cancer drugs lack specificity for tumor cells. After intravenous injection, they are quickly eliminated in the blood and rapidly distributed into various organ tissues, especially liver, kidney, intestine and other tissues, thereby resulting in severe toxic side effects which mainly include nephrotoxicity, digestive tract toxicity (nausea, vomiting), bone marrow toxicity, neurotoxicity and ototoxicity, and the like. Moreover, it has disadvantages, for example, the drug reaches the tumor site at a relatively low concentration, reducing its efficacy; and long-term administration will also cause tolerance in cancer cells, thereby reducing the chemotherapeutic effect.
In order to solve the above problems, it is necessary to prolong the circulation time of the drug in the blood and reduce non-specific binding between drugs and proteins, thereby reducing the systemic toxic side effects and improving the pharmaceutical efficacy. Pharmaceutical researchers in many countries have devoted themselves to the study on the targeting delivery system of platinum-based drugs, such as micelles, vesicles, liposomes, and nanoparticles. These drug carriers can effectively entrap the drug therein for delivery and control the release of the drug by taking advantage of the properties of carriers, thereby increasing the effective accumulation of the drug at the target site and reducing the concentration thereof in non-lesion sites, which can both improve the therapeutic efficacy and reduce the systemic side effects.
In the prior art, many methods for developing a platinum-based preparation by entrapping the drug in a carrier have been disclosed. For example, Uchino et al., have prepared a micelle with a drug loading of 30 wt. % (NC-6004) by complexing cisplatin with carboxyl group-rich polyethylene glycol-b-polyglutamic acid, which has entered into phase II clinical trials [British Journal of Cancer (2005) 93, 678-687]. However, since the resulting micelle is formed by cross-linking between the side chains of polyamino acids, the lyophilized powders of the complex obtained by this method is very difficult to re-dissolve after freeze-drying and the efficacy of the preparation is not improved. Access Pharmaceuticals prepared AP5280 by combining the commonly used polymer HPMA with cisplatin, which has an accumulation at tumor sites 19 times of the cisplatin injection and significantly reduced the nephrotoxicity of cisplatin [J. Drug Target 10 (2002) 549-556]. These studies have shown that platinum compounds can bind to macromolecules through chemical bonds sensitive to environment, thereby effectively reducing the toxicity of platinum-based drugs and improving the therapeutic efficacy thereof. Moreover, the chemical bonds sensitive to environment are critical to the pharmaceutical efficacy of platinum-based anticancer drugs, because they can change the hydration rate of platinum compounds in vivo. The faster platinum compounds are hydrated in vivo, the stronger the antitumor effect thereof is, and however at the same time, the higher the toxicity thereof is. Poulomi Sengupta et al. showed that the pharmaceutical effect produced by combing cisplatin with cholesterol-maleic anhydride via monocarboxylato and O→Pt bond is significantly superior to that of the complex formed by combining cisplatin with macromolecules via stable dicarboxylato bond, and however a greater toxicity may be produced therefrom. To this end, researchers try to prepare platinum-based anti-tumor drugs into liposomes in order to change the distribution of drugs in vivo, reduce adverse reactions and expand the scope of application.
However, platinum-based anti-tumor drugs are very difficult to be prepared into liposomes. Taking cisplatin as an example, there are two major problems in the preparation of liposomes thereof. Firstly, cisplatin has solubility in water of about 1 mg/mL at 4° C. Secondly, cisplatin can only be prepared into liposomes by passive loading, and thus pH gradient active loading cannot be performed by reference to the marketed doxorubicin liposome Doxil and the like. The above two reasons usually lead to a low drug loading of cisplatin liposomes. The cisplatin long-circulating liposome (SPI-077) developed by ALAZA, is a PEGylated liposome, which increases the solubility of cisplatin mainly by heating. In the preparation of SPI-077, hydration is performed at a high temperature of 65° C., allowing an increase in the solubility of cisplatin by about 8 mg/mL. However, the cisplatin long-circulating liposome prepared by this method still has a very low drug loading. For SPI-077, the drug can only be released by degrading the lipid bilayer by lipase. Therefore, there are few free drugs to be released from liposomes and enter into the extracellular fluid of the tumor cells, thereby leading to a decrease in antitumor activity [Advanced Drug Delivery Reviews, 2013, 65(13-14): 1667-1685].
It follows that, the existing techniques still cannot solve the above-mentioned problems of platinum compounds, and cannot improve the drug loading while maintaining a good activity of the drug and moreover reducing toxic side effects thereof.